Disentangling the aetiological pathways between body mass index and site-specific cancer risk using tissue-partitioned Mendelian randomisation

Background Body mass index (BMI) is known to influence the risk of various site-specific cancers, however, dissecting which subcomponents of this heterogenous risk factor are predominantly responsible for driving disease effects has proven difficult to establish. We have leveraged tissue-specific gene expression to separate the effects of distinct phenotypes underlying BMI on the risk of seven site-specific cancers. Methods SNP-exposure estimates were weighted in a multivariable Mendelian randomisation analysis by their evidence for colocalization with subcutaneous adipose- and brain-tissue-derived gene expression using a recently developed methodology. Results Our results provide evidence that brain-tissue-derived BMI variants are predominantly responsible for driving the genetically predicted effect of BMI on lung cancer (OR: 1.17; 95% CI: 1.01-1.36; P = 0.03). Similar findings were identified when analysing cigarettes per day as an outcome (Beta = 0.44; 95% CI: 0.26-0.61; P = 1.62 x 10(-6)), highlighting a possible shared aetiology or mediator effect between brain-tissue BMI, smoking and lung cancer. Our results additionally suggest that adipose-tissue-derived BMI variants may predominantly drive the effect of BMI and increased risk for endometrial cancer (OR: 1.71; 95% CI: 1.07-2.74; P = 0.02), highlighting a putatively important role in the aetiology of endometrial cancer. Conclusions The study provides valuable insight into the divergent underlying pathways between BMI and the risk of site-specific cancers.

Automated summary

This study uses tissue-specific gene expression to separate the effects of different phenotypes underlying BMI on the risk of site-specific cancers. The results suggest that BMI variants derived from brain tissue are predominantly responsible for driving the genetically predicted effect of BMI on lung cancer, while BMI variants derived from adipose tissue may predominantly drive the effect of BMI on endometrial cancer.